Process for the production of cyclopentanophenanthrene derivatives



United States Patent 2,842,543 PROCESS FOR THE PRODUCTION OF CYCLO- PENTANOPHENANTHRENE DERIVATIVES A portion of the process of the present invention is set forth in the following equation wherein lithium metal is used as the reducing agent by way of illustration although other alkali metals may also be used:

Carl Djerassi, Birmingham, Mich., and Franz Sondheimer OH and George Rosenkranz, Mexico City, Mexico, as-

signors to Syntex, S. A., Mexico City, Mexico, a corporation of Mexico \0 No Drawing. Original application April 25, 1953, Serial No. 425,310, now Patent No. 2,781,365, dated Febru- 10 ary 12, 1957. Divided and this application November 16, 1956, Serial No. 626,792

Claims priority, application Mexico April 25, 1953 7 Claims. c1. zen-239,55 EE The present invention relates to the production of novel omo- $15 ,3 s cyclopentanophenanthrene derivatives and to a novel process for the production thereofi This application is a division of application Serial No.

425,310, now Patent No. 2,781,365. CH3

More particularly the present invention relates to the production of the novel active cortical hormone 19-nor- I..

17a-hydroxyprogesterone (A -19=nor-pregnen-17a-ol-3,20- dione) and to the production of novel intermediates convertible thereto. As pointed out in application Serial Number 425,300 filed as of even date herewith l9-norv V 17a-hydi-oxyprogesterone is also useful as an intermediate forthe production ofthe active cortical hormone A -19- Q:

nor-pregnen-l15,17u,2l-triol-3,20-dione by incubation wit adrena tissue.

1 1 1 accordance with the present invention it has been In practicing the steps above Set forth the zo'ketal of discovered that a novel intermediate, i. e. the 20-ketal of g i g g z a gg g ggg gf g g ig ig gi ig gg 3 methoxy 17a hydroxy 17,8 acetyl 1,3,5(10')- v estratriene upon reduction with lithium metal or other P i t and adqed dropwlse to lithium metal alkali metal in liquid ammonia gives a Second novel n dissolved in liquid ammonia. After a short time methanol termediate, i. e. the ZO-ketal of 3:-methoxy-17a -hydroxywas added,and the ammonia was then allowed P Ammo9 nor pregnadien 20 one which may then be com rate overnight at room temperature. After purification verted to the novel cortical hormone l9-nor-17a-hydrox'yas hereinafter set g the 20 1.(eta1 of i progesterone. hydroxy-UB-acetyl-A I -estradiei ie was obtained. Hy-

It has further been discovered in accordance with the drolysls and rearraPgemFnt of thls ketal Wlth an acld present invention that the intermediate ZO-ketal of 3- 40 Such as hydlfochlollc 361d P oduced A -19-nor-pre nenmethoxy 17a hydroxy acetyl 135mm, estra l7a-ol3,20-dione (l9-nor-l7u-hydroxyprogesterone). triene may be prepared by novel methods from the known The zo'ketal of compounds 3 hydroxy 17,8, acetyl asx1 1.,3,5(10)*-6Stl3tfl6116 may be prepared from e ther 3 estratetraene and 3,17 dihydroxy i7 acetyl 1,3,5 hydroxy acetyl estratetraene or (10)-estratriene disclosed in the publication of Djerassi y y- Y y as et al., J. A. C. S. 73, 1526 (1951). lined 'i e following equation:

i/fgzrlcixyllene VIII VI Ethylene glycol Lithium 1 ran As may be noted by referring to the foregoing equation the ZO-ketal of 3-methoxy-17a-hydroxy-l7B-acetyl-1,3, 5 (lO)-estratriene indicated as V may be prepared from 3-hydroxy-17B-acetyl-l ,3,5(), l6-estratetraene indicated as I by either of the paths I, II, III, IV and V, or I, II, III,

catalytic reduction to form compound VII and then this last compound is reacted with ethylene glycol for example to form compound V. The last of the three paths enumerated is entirely similar to the first path except that the order of the various steps is changed. Thus, the reaction with the glycol to form the ketal (II to VIII) is performed prior to the reaction with methyl sulfate and the reduction of the oxido group with lithium aluminum hydride also precedes the reaction with methyl sulfate.

In addition to the above discussed procedures for the preparation of the compound indicated as V, it may be noted that by starting from 3,l7u-dihydroxy-17-acetyl-l,3, 5(10)-estratriene (X) which is already provided with a l7a-hydroxy group certain steps may be eliminated and only the reaction with the glycol (X to IX) followed by reaction with methyl sulfate (IX to V) is necessary.

It may be noted further than the conditions involved in each of the similar steps above outlined are the same in all essential respects. For the reaction of. 3/3-hydroxyl7p-acetyll,3,5 (10), l6-es'tratetraene (I) with hydrogen peroxide, the steroid is dissolved in an organic solvent such as methanol, the solution cooled and hydrogen peroxide as well as aqueous alkali such as sodium hydroxide added separately and slowly thereto. The reaction mixture was allowed to stand in the cold for a short time and then overnight at room temperature. After purification the product was 16a,17a-oxido-3B-hydroxyl7,l3-acetyl-l,3,5(10)-estratriene (II).

For the reaction with methyl sulfate of 16oz, 17oz-OXiCl0- 3B-hydroxy-17,8-acetyl-l,3,5(lO)-estratriene (II) to form 16u,l7u-oxido-3-methoxy 17,8 acetyl-l,3,5 (10) estratriene (III) or the ZO-ktal of 3,1la-dihydroxy-l7 8-acetyl- CH; t IV i m?) [Lithium aluminum hydride 1,3,5 (l0)-estratriene IX to give the compound (V), the starting steroid was dissolved in an organic solvent such as methanol and treated with a strong base such as potassium hydroxide and methyl sulfate. 35 In order to form the 20-ketal group the starting steroid such as 16a,17a-oxido-3-methoxy-17,8-acetyl-1,3,5 (10)- estratriene (III) or 16a,l7a-oxido-3B-hydroxy-17,8-acety1- 1,3,5(10)-estaratriene (II) or 3-methoxy-l7a-hydroxy- .17,8-acetyl-1,3,5(l0)-estratriene (VII) or 3,17m-dihydroxy-17 3-acetyl-1,3,5(10)-estratriene (X) was dissolved in an organic solvent, such as benzene, containing ethylene glycol and a catalytic amount of a strong organic acid such as p-toluenesulfonic acid and refluxed for a prolonged period such as ten hours. Purification gave the corresponding compounds IV, VIII, V and IX respectively.

The 16u,17a-oxido group as may be noted from the equation can be converted to a 17a-hydroxy group by reduction with lithium aluminum hydride (compound IV to V and compound VIII to IX) or by adding HBr followed by catalytic reduction to remove the l7-bromo group of the bromohydrin (compound HI to VI to VII).

For the reaction with lithium aluminum hydride the starting steroid the ZO-ketal of 160:,17u-0Xid0-3-II16I110XY-17,3- acetyl-1,3,5(10)-estratriene (IV) or the 20-ketal of 16a, 17cc-OXld0-3B-hYdI'OXY-17fi-ac6ty1 1,3,5 10) estratriene (VIII) is dissolved in an anhydrous organic solvent such as tetrahydrofurane and refluxed with lithium hydride which is added in an organic solvent such as ether. The excess hydride is decomposed, and the products (V or IX) precipitated and purified.

For the reaction of 16a,l7a-oxido-3-methoxy-17fl-acety1-1,3,5(10)-estratriene (III) with HBr the compound is dissolved in acetic acid and a solution of hydrobromic acid in acetic acid added thereto while the temperature is maintained just below room temperature. The solution is'then allowed to stand for a short time at room temperature and is then poured into cold water to pre cipitate the bromohydrin i. e. 16-bromo-3-rnethoxy-17ahydroxy-17fi-acetyl-l,3,5(l0)-estratriene (VI). The bromohydrin is then treated with hydrogen in the presence of a hydrogenation catalyst, preferably a palladium catalyst until 1 mol of hydrogen is absorbed. Upon purifica- 75 tion the compound VII is produced.

The following specific examples serve to illustrate but are not intended to limit the .present invention:

Example I Toa solution of 3 g. of 3-hydroxy-17-acetyl-1,3,5(l0), l6-estratetraene (I) in 100 cc. of methanol, cooled in an ice bath, was added dropwise andsimultaneously from two separatory funnels 6 cc. of 30% hydrogen peroxide and a solution ,of 4 g of sodium. hydroxide in 15 cc. of water. The two solutions were added in a period of approximately 15 minutes. The mixture was kept for 30 minutes in the cold andthen overnight at room temperature. After diluting with Water and acidifying the product was extracted with chloroform and the chloro-' form solution was dried over sodium sulphate and evaporated to dryness. Recrystallization from chloroformmethanol yielded 3 g. of the 16,17-epoxide (II) with a melting point of 234236 C.; [41] +124 (chloroform).

Example II A boiling solution of 2.5 g. of the 16,17-epoxide (II), obtained in accordance with Example I, in 180 cc. of methanol was alternatively treated with four portions of 7 cc. of 50% potassium hydroxide and 7 cc. of methyl sulfate. After ten minutes, the solution was cooled, diluted with water and the precipitate was collected and well washed with water. Crystallization from acetone-hexane afforded 2.5 g. of the methyl ether (III) with melting point 142-145 C. [ecl +l25 (chloroform).

Example III A solution of 3 g. of the methyl ether (III), obtained in accordance with the previous example, in 60 cc. of benzene containing 6 cc. of ethylene glycol and a trace of ptoluenesulfonic acid, was refluxed for ten hours using an adapter for the removal of the water formed in the course of the reaction. Dilute potassium hydroxide solution was added and the benzene layer was repeatedly washed with Water, dried and evaporated to dryness. Recrystallization from acetone-hexane gave the 20-ketal (IV).

Example IV 0.3 g. of lithium aluminum hydride in 10 cc. of anhydrous ether was added to a solution of 3 g. of the ketal, obtained in accordance with the previous example, in 50 cc. of tetrahydrofurane. The solution was refluxed for one hour and the excess of hydride was decomposed by the addition of ethyl acetate. Then a saturated solution of sodium sulfate was added, followed by 3 g. of solid sodium sulfate. The precipitate was filtered and washed with ether and the combined filtrates were evaporated to dryness. Crystallization from acetone-pentane afforded the 20-ketal of 3-methoxy-17a-hydroxy-17,3- a-cetyl 1,3,5 (10) estratriene (V) with melting point 124126 C.; [M +44 (chloroform).

Example V 3 g. of the 16,17-epoxide (II) obtained in accordance with Example I, was treated with ethylene glycol by the procedure described in Example III. The resulting ketal (VIII) was treated with lithium aluminum hydride by the procedure described in Example IV, to give the ZO-ketal of 3,17a-dihydroxy-17B-acetyl-l,3,5 l)-estratriene (IX), which on treatment with methyl sulfate, by the procedure described in Example 11, produced the 20-ketal of 3- methoxy-l7a-hydroxy-17B-acetyl 1,3,5 (10) estratriene (V) identical to the one obtained in accordance with Example IV.

Example VI 3 g. of 3,17a-dihydroxy-17/3-acetyl-l,3,5(10)-estratriene (X) was treated with ethylene glycol, by the procedure described in Example III to give 1.7 g. of the 20- ketal (IX), identical to the one obtained in accordance with Example V.

6 Example VII To a solution of 1 g. of 3-methoxy-16u,17a-oxido-17pacetyl-1,3,5(10)-estratriene (III) prepared according to Example H, in 10 cc. of acetic acid, there were added 2 cc. of a 32% hydrobromic acid solution in acetic acid while maintaining the temperature constant between 15 and 18 C. The solution was allowed to. stand for 15 minutes at room temperature and is emptied into 15 times its volume of iced water with agitation in order to obtain a uniform precipitation. The precipitate was filtered, washed to neutrality and dried at room temperature. The yield of bromohydrin (VI) was almost quantitative.

1 g, of the bromohydrin thus obtained was agitated in an atmosphere of hydrogen at atmospheric pressure with 3 g. of 2% previously reduced palladium hydroxide upon calcium carbonate and 20 cc. of ethanol previously distilled over Raney nickel. In the course of two hours there was absorbed the equivalent of one mol of hydrogen. The precipitate was filtered and Washed with water. The dry product wascrystallized from acetone-hexane. 0.8 g. of 3-methoxy-l7a-hydroxy--l7/3-acetyl1,3,5(10)- estratriene (VII) with a melting point of -152 C. [all 45 (chloroform) was obtained.

Example VIII To 3.3 g. of 3-rnethoxy-l7a-hydroxy-l7fi-acetyl-l,3, 5(10)-estratriene (VII) dissolved in 200 cc. of anhydrous benzol there was added 40 cc. of ethylene glycol and 0.22 g. of p-tolnenesulfonic acid. The solution was refluxed with stirring for 8 hours, chilled, then washed with a solution of sodium bicarbonate and water and evaporated to dryness. By crystallization from pentane there was obtained the ZO-ketal of 3-methoxy-17a-hydroxyl7fl-acetyl-1,3,5(10)-estratriene (V) in a yield of 3.03 g. with a melting point of l20-l23 C. [al +40 (chloroform) identical to that obtained according to Examples IV, V and VI.

Example IX 1.4 g. of lithium metal (wire) was dissolved in 150 cc. of liquid ammonia in a Dewar flask fitted with a mechanical stirrer, and then a solution of 1.4 g. of the ZO-ketal of 3-methoxy-17a-hydroxy-17fl-acetyl 1,3,5(10) estratriene, in 150 cc. of anhydrous ether was added dropwise in the course of approximately five minutes. After ten minutes longer, 16 cc. of absolute methanol was added dropwise in the course of 20 minutes. The ammonia was allowed to evaporate overnight at room temperature and the residue Was collected with cold water and extracted With ethyl ether. The ether extract was washed to neutral, dried and evaporated to drynesss. Recrystallization from acetone-hexane yielded 1.0 g. of the 20-ketal of 3-rnethoxy-17a-hydroxy 17 8 acetyl- A -estradiene melting point 175 -176 C. (Kofler); [al +74 (chloroform).

Example X 30 cc. of a 3 N solution of hydrochloric acid was added to a solution of 1 g. of the 20-ketal of 3-methoxy-17ahydroxy-l9-nor-A -pregnadien-20-one in 50 cc. of methanol and the mixture was heated at a temperature of 60 C. for 15 minutes. The cooled mixture was mixed with water and ether and the ether layer was washed with sodium bicarbonate solution and water until neutral, dried over sodium sulfate and exaporated to dryness. Upon crystallization from acetone A -l9-nor-pregnenl7a-ol-3,20-dione is obtained having a melting point of 204-206 C.; [04],; +41 (chloroform) which showed the typical ultraviolet absorption maximum at 240 m (log E 4.20).

We claim:

1. A process for the production of the ZO-ketal of 3- methoxy-17a-hydroxy-17 8-acetyl 1,3,5 (10) estratriene which comprises treating ,17ot-0Xid0-3-I116th0XY-17B- acetyl-1,3,5(l0) estratriene with hydrobromic acid to 7 form 16-bromo-3-rnethoxy-17a-hydroxy-17fi acetyl 1,3, 5(10)-estratriene, treating the 16-bromo compound with hydrogen in the presence of a hydrogenation catalyst to remove the 16-bromo group and form 3-methoxy-17ahydroxy-17B-acetyl 1,3,5(10)-estratriene and treating this last mentioned compound with a ketalizing agent.

2. The process of claim 1 wherein the hydrogenation catalyst is a palladium catalyst and the ketalizing agent is ethylene glycol in the presence of a strong organic acid.

3. A process for the production of the ZO-ketal of 3- methoxy-17u-hydroxy-17fi-acetyl 1,3,5(10) estratriene which comprises treating 3,17u-dihydroxy-17,3-acety1-1,3, 5(10)-estratriene in indifierent order with a methylating 8 agent to form the 3-methoxy group and with a ketalizing agent to form the 20-ketal group.

4. The process of claim 2 wherein the methylating agent is methyl sulfate and the ketalizing agent is ethylene glycol in the presence of p-toluenesulfonic acid.

5. 16a,17a-oxido-3-hydroxy-17B-acety1 1,3,5 10) estratriene.

6. The 20-ketal of 3-rnethoxy-17u-hydroxy-17fl-acetyl- 1,3,5 10)-estratriene.

7. The ZO-ketal of 3-rnethoxy-17a.-hydroxy-A=' -19- nor-pregnadien-ZO-one.

No references cited. 

1. A PROCESS FOR THE PRODUCTION OF THE 20-KETAL OF 3METHOXY-17A-HYDROXY-17B-ACETYL - 1,3,5(10) - ESTRATRIENE WHICH COMPRISES TREATING 16A,17A-OXIDO-3-METHOXY-17BACETYL-1,3,5(10) ESTRATRIENE WITH HYDROBROMIC ACID TO FORM 16-BROMO-3-METHOXY-17A-HYDROXY-17B-ACETYL - 1,3, 5(10)-ESTRATREINE, TREATING THE 16-BROMO COMPOUND WITH HYDROGEN IN THE PRESENCE OF A HYDROGENATION CATALYST TO REMOVE THE 16-BROMO GROUP AND FORM 3-METHOXY-17AHYDROXY-17B-ACETYL 1,3,5 (10)-ESTRATRIENE AND TREATING THIS LAST MENTIONED COMPOUND WITH A KETALIZING AGENT. 